Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(Cl)cc(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.20 g, 55% yield), mp=112–114° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.4° (c=1, EtOH).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1([C:11]([C:13]#[N:14])=[O:12])[CH2:10][CH2:9]1)[CH3:7].[OH2:15]>C(O)(C)(C)C.C(Cl)Cl>[C:8]([NH:14][C:13](=[O:15])[C:11]([C:8]1([CH2:6][CH3:7])[CH2:10][CH2:9]1)=[O:12])([CH3:10])([CH3:9])[CH3:6]
Reactant: O
Reactant: CCC1(C(=O)C#N)CC1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCC1(C(=O)C(=O)NC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of H2SO4 (98%) is added dropwise at 0°-5° C., in the course of 10 minutes, to a solution of 12.3 g of 1-ethylcyclopropanecarboxylic acid cyanide in 13 g of tert-butanol and 13 ml of methylene chloride. The solution is subsequently stirred for 4 hours at room temperature; 2 ml of H2O is then added and stirring is continued for a further 30 minutes. The pH value of the solution is brought to 6 with 80 ml of ZnNaOH, and the organic phase is separated. After removal of the solvent, the residue is crysrallised out from 50 ml of petroleum ether (b.p. 40° to 65° C.) at 50° C. to thus yield 13.1 g of white crystals of pure (1-ethylcyclopropyl)-glyoxylic acid tert-butylamide having a melting point of 37.5°-39° C.
Reaction SMILES: [Br:1][C:2]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1([CH2:5][CH2:6][O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCCC1(Br)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the cyclopropyl alcohol (Step A) (1.303 g, 7.95 mmoles) in 30 ml anhydrous DCM was added anhydrous pyridine (1.2 ml, 1,1736 g, 14.8 mmoles), TBSOTf (2.7 ml, 3.1077 g, 11.76 mol) and the solution was stirred at room temperature for 16 h. It was extracted with CHCl3/brine and the organic fraction was dried with MgSO4. The solvent was reduced and the crude product purified using flash-column chromatography (CHCl3/hexanes 1:10, Rf=0.4). Yield: 0.796 g, 36%. 1H-NMR (500 MHz, CDCl3): δ=3.95-3.75 (t, 2H), 1.95-1.85 (t, 2H), 1.15-1.05 (m, 2H), 0.95-0.80 (m, 11H), 0.15-0.05 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].[C:17]([O:24][CH2:25][CH3:26])(=[O:23])[C:18](OCC)=O.[CH2:27]([NH:29][NH2:30])[CH3:28]>>[CH2:27]([N:29]1[C:18]([C:17]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[N:30]1)[CH3:28]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNN
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC
Yield: 92 %

Procedure:
Using 1-[4-(trifluoromethoxy)phenyl]ethanone (13.0 g), sodium hydride (60%, oily, 2.8 g), diethyl oxalate (8.7 mL) and ethylhydrazine (4.2 g) and in the same manner as in Example 56(1), the title object compound (19.4 g, 92%) was obtained as an oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[CH3:24][C:25]1([CH3:43])[CH:34]([N:35]2[C:39]([CH:40]=O)=[CH:38][N:37]=[CH:36]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:42])[O:26]1>C1COCC1>[CH:40]([C:39]1[N:35]([CH:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:42])[O:26][C:25]2([CH3:43])[CH3:24])[CH:36]=[N:37][CH:38]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propyltriphenylphosphonium bromide (0.157 g, 0.41 mmol) in THF (1 mL) at −78° C. is added sodium hexamethyldisilylamide (1M in THF, 0.44 mL, 0.44 mmol) and the mixture is allowed to warm to ambient temperature over 10 min. This solution is cooled to −20° C. and 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.10 g, 0.37 mmol) in THF (0.2 mL) is added. The cooling bath is removed and the mixture is stirred at ambient temperature overnight, then filtered. The filtrate is concentrated in vacuo to give the crude 4-(5-but-1-enyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one which is used in the next step without further purification; MS (ESI) m/z 297.1 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[N:14]=[CH:13]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:26].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1>[Br:26][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(C(=O)Cc3ccccc3)ccc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(c1ccc2[nH]ncc2c1)C(Br)c1ccccc1

Procedure:
To a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL) heated at 40° C. with an oil bath was added dropwise with an addition funnel a solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) over 10 minutes. The reaction mixture was heated for an extra 2 hours, and was cooled, filtered, and the filtrate was evaporated to afford the title compound. MS (ESI−) m/z 212.9 (M−H)−.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+]>O.Cl>[Br:8][C:7]1[C:2](=[O:11])[NH:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
A solution of 2-amino-3-bromo-5-chloropyridine (4.0 g, 19.3 mmol) in water (30 mL) and conc. HCl (5.2 mL) was cooled with an ice bath to 0° C. and was treated with a solution of sodium nitrite (1.33 g, 19.3 mmol) in water (12 mL) over 10 min. The mixture was stirred for an additonal 10 min and allowed to warm to room temperature over 48 hr. The mixture was filtered. The solids were washed with water, then with CCl4 and were dried under vacuum at 50° C. for 3 hr to give 3-bromo-5-chloro-1H-2-pyridone (2.77 g, 69%), mp 173.5-175° C.
Reaction SMILES: [Al](OC(C)C)(OC(C)C)OC(C)C.S(=O)(=O)(O)O.CC(O)C.[CH3:23][C:24](=[CH:27][CH2:28][CH:29]1[CH2:33][CH:32]=[C:31]([CH3:34])[C:30]1([CH3:36])[CH3:35])[CH:25]=[O:26]>CC(C)=O>[CH3:23][C:24](=[CH:27][CH2:28][CH:29]1[CH2:33][CH:32]=[C:31]([CH3:34])[C:30]1([CH3:36])[CH3:35])[CH2:25][OH:26]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(=CCC1CC=C(C)C1(C)C)CO
Temperature: 85 °C
Reaction time: 7 h
Yield: 88 %

Procedure:
10.2 g (50 mmol) of Al(O-i-Pr)3, 0.25g (2.5 mmol) of sulfuric acid and 180 g (3.0 mol) of IPA were fed into a 1000 ml four-necked round bottom flask under atmosphere of nitrogen, and stirred at 85° C., and then 192 g (1.0 mol) of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al was added. The reaction was conducted while fraction containing acetone generated at the solution temperature of 85° to 95° C. was removed by distillation. After 7 hours, the reaction solution was analyzed by GLC, 88% of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol was obtained (corresponding to 92% selectivity for conversion of the aldehyde as the starting material).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C([O-])(O)=O.[Na+].[CH3:27][C:28](OC(C)=O)=[O:29]>C1(C)C=CC=CC=1.CC#N>[C:28]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:29])[CH3:27]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Yield: 98.8 %

Procedure:
A mixture of morphine (23.63 g, 83 mmol), NaHCO3 (28.2 g, 336 mmol), Ac2O (8.69 g, 85 mmol) in toluene (500 ml) and CH3CN (900 ml) was heated at reflux for 21 hrs. The reaction mixture was evaporated to dryness in vacuo. To the residue was added water (80 ml) and extracted with chloroform (500 ml). The extracts were dried, combined and evaporated to dryness in vacuo to obtain a residue, which was chromatographed on silica gel (column: d=6 cm, I=8 cm, packed with 141 g of silica gel; solvent system: 5-10% MeOH in CH2Cl2) to yield 3-acetylmorphine (27 g, 100% yield). IR (KBr)(ν, cm-1): 3500 (m, sharp, --OH), 1750 (s, sharp, AcO); NMR (δH)(CDCl3): 6.73(1, d, J, 8.1,2-H), 6.57(1, d, J, 8.1, 1-H), 5.74(1, dm, J, 10.1,7-H), 5.25 (1, dm, J, 9.9, 8-H), 4.91 (1, d, J, 6.9, 5-H), 4.25-4.10 (1, m, 6-H), 3.50-3.35 (1, m, 9-H), 3.05(1, d, J, 19.1, 10-Hβ), 2.8-2.7 (1, m, 14-H), 2.85-2.60 (1, m, 16-He), 2.50-2.25 (1, m, 16-Ha), 2.45 (3, s, NCH3), 2.5-2.2 (1, m, 10-Hα), 2.28 (3, s, AcO), 2.06 (1, td, J, 12.1 & 5.0, 15-Ha), 2.0-1.85 (1, m, 15-He).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (320 mg) in N,N-dimethylformamide (2.0 mL), was added potassium carbonate (452 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodomethane (444 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (325 mg) as a pale-yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15])=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:15][C:7]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1c(NC(=O)CBr)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-N-(2-methyl-3-nitrophenyl)acetamide (0.5 g, 1.8 mmol) was dissolved in 15 ml of THF and to this was added morpholine (0.17 g, 2.0 mmol) and diisopropylethylamine (0.71 g, 5.5 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between EtOAc and H2O. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with H2O, brine and then dried over MgSO4. Solvent evaporation afforded N-(2-methyl-3-nitrophenyl)-2-morpholinoacetamide as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2C(=O)[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C.[CH3:36][OH:37]>C1COCC1>[OH:28][NH:27][C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:36](=[O:37])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(NO)c1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Yield: 91 %

Procedure:
A solution of 5-(3-cyanophenyl)-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (37 mg, 0.11 mmol), hydroxylamine hydrochloride (76 mg, 1.1 mmol) and triethylamine (0.16 mL, 1.1 mmol) in THF (0.65 mL)/methanol (1.3 mL) was heated under reflux for 2 hours. The solvent was removed under reduced pressure, and to the residue was added water (4 mL). The precipitated crystal was filtered and washed with water. The crystal was dried in vacuo at 50° C., to give the titled compound as a light gray crystal (36 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00 g, 3.63 mmol) in DCM (20 mL), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.30 g, 4.03 mmol) was added and the reaction mass was stirred at RT for 2 h. After completion of reaction, excess of solvent was removed under reduced pressure to obtain 0.700 g of the crude product. To a solution of obtained crude product in DCM (5.0 mL), TFA (5.0 mL) was added and the reaction mass was stirred at RT for 2-3 h. Excess of the solvent was removed from the reaction mass under reduced pressure and the reaction mass was quenched in ice and filtered to obtain 0.700 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 4.45 (d, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.65-7.68 (m, 2H), 8.85 (d, J=6.6 Hz, 2H), 8.18 (d, J=6.3 Hz, 2H), 10.05 (s, 1H), 12.69 (s, 1H); MS (m/z): 463.17 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][O:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19].C(N(CC)CC)C>CN1C(=O)CCC1.CCOC(C)=O>[CH3:15][O:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: COC(C)(C)CN
Reactant: CSc1ncc2cc(C)nc(Cl)c2n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(C)(C)CNc1nc(C)cc2cnc(SC)nc12
Temperature: 120 °C
Yield: 60.9 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 52, 80 mg, 0.354 mmol) in NMP (7 mL) was added 2-methoxy-2-methylpropan-1-amine (0.086 ml, 0.709 mmol) and triethylamine (0.249 mL, 1.772 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to afford the title compound (63 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]1)[CH:6]=[C:5]2CC=C.C[N+]1([O-])CC[O:30]CC1.[CH3:34][C:35]([CH3:37])=[O:36]>O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]1)[CH:6]=[C:5]2[CH2:34][CH:35]([OH:36])[CH2:37][OH:30]
Reactant: C=CCc1cc(N2CCCc3ccccc3C2)nc2ccc(Cl)cc12
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: OCC(O)Cc1cc(N2CCCc3ccccc3C2)nc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[6-chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine (20 mg, 0.057 mmol) in acetone (2 mL) and water (1 mL) was added N-methyl morpholine-N-oxide (50% in water, 15.5 mg, 0.057 mmol) followed by osmium tetroxide (0.14 mg, 0.0005 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 3:2) to give 14 mg of product as colorless oil. MS obsd. (ESI+) [(M+H)+] 383. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=2.0 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H), 7.50 (d, J=6.8 Hz, 1 H), 7.40 (dd, J=9.2, 2.4 Hz, 1 H), 7.14-7.08 (m, 4 H), 4.84 (brs, 2 H), 4.21 (brs, 1 H), 4.10 (brs, 1 H), 3.91-3.88 (m, 1 H), 3.58-3.55 (m, 2 H), 3.21 (dd, J=14.0, 4.4 Hz, 1 H), 3.04 (d, J=6.4 Hz, 2 H), 2.87 (dd, J=14.0, 8.4 Hz, 1 H), 1.91-1.86 (m, 2 H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:17](=[O:18])[O:16][C:14](=[O:15])[C:7]2=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O.N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].N(O[CH2:30]CCCC)=O>CN(C)C=O>[CH:4]1[C:13]2[C:12]3[CH2:30][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26][C:11]=3[CH:10]=[CH:9][C:8]=2[C:7]2[C:14]([O:16][C:17](=[O:18])[C:6]=2[CH:5]=1)=[O:15]
Reactant: Nc1ccccc1S
Reactant: CCCCCON=O
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])c1ccccc21
Solvent: CN(C)C=O
Product: O=C1OC(=O)c2c1ccc1c3c(ccc21)Sc1ccccc1C3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension was prepared by mixing 48.6 g of 4-nitronaphthalene dicarboxylic anhydride in 1,000 ml of dimethylformamide, to which 38.0 g of 2-aminobenzenethiol was added dropwise at room temperature over 30 minutes. After the completion of addition, 30 ml of amyl nitrite was added with stirring over 30 minutes and mixed for another 45 minutes. After cooling to room temperature, it was recrystallized with dimethylformamide to obtain a crystal of benzothioxanthene-3,4-dicarboxylic anhydride. The obtained crystal was reacted with p-dimethylaminophenylacetic acid and potassium acetate to obtain a reaction product. Then, 45.2 g of the reaction product was dissolved in 200 ml of dimethylformamide and 8.4 g of anhydrous potassium carbonate was added, followed by heating to reflux for 30 minutes. Produced water was removed and the resultant mixture was cooled to 60° C. before 25.2 g of diethyl sulfate was added for 2 hours and mixed at 60° C. for 2 hours. After cooling, methanol was added to the reaction solution and the precipitated solid was filtered and dried to obtain a sensitizer (a-1) shown in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(Br)cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a mixture of 2-bromo-4-methyl-6-nitrophenol (7.00 g, 30.2 mmol), K2CO3 (6.26 g, 45.3 mmol) in acetone (105 mL) was added allyl bromide (3.80 ml, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. It was then heated at 40° C. for 5 hrs. Inorganic salts were filtered and washed with acetone. The filtrate was concentrated to give 7.74 g (94%) of the desired product. MS (DCI/NH3) m/z: 289.0 (M+NH4)+; 1H NMR (300 MHz, CD3OD) δ ppm 2.37 (s, 3 H) 4.61 (d, J=6.10 Hz, 2 H) 5.26 (dd, J=10.51, 1.80 Hz, 1 H) 5.39 (dd, J=17.29, 1.80 Hz, 1 H) 6.09 (m, 1 H) 7.63 (s, 1 H) 7.74 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:23].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:8]1[C:7]2[S:23][C:4]([C:3]3[C:2]([Cl:1])=[CH:18][C:17]([I:19])=[CH:16][C:15]=3[Cl:20])=[N:5][C:6]=2[CH:11]=[CH:10][N:9]=1
Reactant: Fc1c(N=C(Cl)c2c(Cl)cc(I)cc2Cl)ccnc1Cl
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-iodobenzimidoyl chloride (2.94 g, 6.30 mmol), thiourea (1.93 g, 25.3 mmol) and pyridine (1.73 mL, 21.4 mmol) in isopropanol (25 mL) was heated to 90° C. for 3.5 hours. Triethylamine (5.3 mL, 37.8 mmol) was added and the resulting mixture was heated to 90° C. for a further 1.5 h. The reaction was cooled to room temperature and then concentrated under reduced pressure. The resultant residue was partitioned between DCM and water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with MeOH and dried under reduced pressure to give the desired compound (2.33 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.90-7.81 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:27][CH3:26])=[O:25])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Product: CNC(=O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and methyl amine. The title compound was obtained as a white solid (6.1 mg, 29% yield). MS (apci) m/z=356.1 (M+H).